Transcriptional Program of Mouse Osteoclast Differentiation Governed by the Macrophage Colony-stimulating Factor and the Ligand for the Receptor Activator of NFκB

Cappellen, David; Luong-Nguyen, Ngoc-Hong; Bongiovanni, Sandrine; Grenet, Olivier; Wanke, Christoph; Šuša, Mira

doi:10.1074/jbc.m200434200

Cited by 172 publications

(130 citation statements)

References 60 publications

(57 reference statements)

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“…Specifically TNF␣ has been shown to up-regulate PLAA and CASP6 (51,52), both of which increased after IR in the wild type but not in the mutant. Decreased TNF␣ activity in p53 K317R thymocytes is also consistent with the observed lack of change in WARS, TCF7, and ETFDH protein levels after IR; all of these proteins are indirectly regulated by TNF␣ (53)(54)(55)(56)(57)(58). Finally TNF␣ has been shown to induce the expression of TGF␤1 (59), which has been shown to increase the expression of FABP5 and SSRP1 (60,61), two additional proteins that exhibit the same pattern.…”

Section: Discussionsupporting

confidence: 62%

Quantitative Proteomics Analysis of the Effects of Ionizing Radiation in Wild Type and p53K317R Knock-in Mouse Thymocytes

Jenkins

Mazur

Rossi

et al. 2008

Molecular & Cellular Proteomics

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The tumor suppressor protein p53 is a sequence-specific transcription factor that has crucial roles in apoptosis, cell cycle arrest, cellular senescence, and DNA repair. Following exposure to a variety of stresses, p53 becomes posttranslationally modified with concomitant increases in activity and stability. To better understand the role of acetylation of Lys-317 in mouse p53, the effect of ionizing radiation (IR) on the thymocytes of p53 K317R knock-in mice was studied at the global level. Using cleavable ICAT quantitative mass spectrometry, the effect of IR on protein levels in either the wild type or p53 K317R thymocytes was determined. We found 102 proteins to be significantly affected by IR in the wild type thymocytes, including several whose expression has been shown to be directly regulated by p53. When the effects of IR in the wild type and p53 K317R samples were compared, 46 proteins were found to be differently affected (p < 0.05). The p53 K317R mutation has widespread effects on specific protein levels following IR, including the levels of proteins involved in apoptosis, transcription, and translation. Pathway analysis of the differently regulated proteins suggests an increase in p53 activity in the p53 K317R thymocytes as well as a decrease in tumor necrosis factor ␣ signaling. These results suggest that acetylation of Lys-317 modulates the functions of p53 and influences the cross-talk between

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Section: Discussionsupporting

confidence: 62%

Quantitative Proteomics Analysis of the Effects of Ionizing Radiation in Wild Type and p53K317R Knock-in Mouse Thymocytes

Jenkins

Mazur

Rossi

et al. 2008

Molecular & Cellular Proteomics

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“…(10)(11)(12)30) c-fms signaling also functions by inducing the expression of a number of OC-associated genes, including RANK. (34) c-Src is also known to play an important role in OC activity in vivo, as demonstrated by c-Src -/-mice, which are severely osteopetrotic owing to an absence of OC activity. (35)(36)(37)(38) While the precise mechanism(s) remain(s) to be elucidated, data shown here (Fig.…”

Section: Discussionmentioning

confidence: 99%

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

Vandyke

Dewar

Diamond

et al. 2010

Journal of Bone and Mineral Research

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Dasatinib is a potent tyrosine kinase inhibitor that is used to treat chronic myeloid leukemia in patients resistant or intolerant to imatinib mesylate. While designed to inhibit Abl and Src kinases, dasatinib shows multitarget effects, including inhibition of the macrophage colony-stimulating factor (M-CSF) receptor c-fms. We have shown previously that dasatinib abrogates osteoclast formation and activity in vitro owing, in part, to its specificity for c-fms. In this study we examined whether dasatinib could significantly alter bone volume in a model of physiologic bone turnover. Sprague-Dawley rats were administered dasatinib (5 mg/kg/day) or vehicle by gavage or zoledronic acid (ZOL; 100 mg/kg/6 weeks) subcutaneously. Following 4, 8, and 12 weeks of treatment, serum biochemical, bone morphometric, and histologic analyses were performed. Whole-body bone mineral density and tibial cortical thickness where unchanged in the dasatinib-or ZOL-treated animals relative to controls. However, micro-computed tomographic (mCT) analysis of cancellous bone at the proximal tibias showed that trabecular volume (BV/TV) and thickness (Tb.Th) were increased in dasatinib-treated animals at levels comparable with those of the ZOL-treated group. These changes were associated with a decrease in osteoclast numbers (N.Oc/B.Pm) and surface (Oc.S/BS) and decreased serum levels of the osteoclast marker c-terminal collagen crosslinks (CTX-1). Mineral apposition rate (MAR), bone-formation rate (BFR), and levels of the serum osteoblast markers osteocalcin and N-terminal propeptide of type I procollagen (P1NP) were not altered significantly in the dasatinib-treated animals relative to controls. These studies show that dasatinib increases trabecular bone volume at least in part by inhibiting osteoclast activity, suggesting that dasatinib therapy may result in dysregulated bone remodeling. ß

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“…19,20,40,41 Although GP Ib-IX expression by osteoclasts has not been directly examined, it seems unlikely because by transcript profiling of cells undergoing osteoclastogenesis GP IX mRNA, a required subunit for surface expression of GP Ib␣, was not found. 42,43 Using immunofluorescence, we have been unable to identify expression of GP Ib-IX in osteoclasts (data not shown). Nevertheless, until proven otherwise, it is likely an oversimplification to assume that the high bone mass phenotype is the result of increased splenic megakaryocytes.…”

Section: Discussionmentioning

confidence: 99%

Platelet Dysfunction and a High Bone Mass Phenotype in a Murine Model of Platelet-Type von Willebrand Disease

Suva

Hartman

Dilley

et al. 2008

The American Journal of Pathology

110

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The platelet glycoprotein Ib-IX receptor binds surfacebound von Willebrand factor and supports platelet adhesion to damaged vascular surfaces. A limited number of mutations within the glycoprotein Ib-IX complex have been described that permit a structurally altered receptor to interact with soluble von Willebrand factor, and this is the molecular basis of platelet-type von Willebrand disease. We have developed and characterized a mouse model of platelet-type von Willebrand disease (G233V) and have confirmed a platelet phenotype mimicking the human disorder. The mice have a dramatic increase in splenic megakaryocytes and splenomegaly. Recent studies have demonstrated that hematopoetic cells can influence the differentiation of osteogenic cells. Thus, we examined the skeletal phenotype of mice expressing the G233V variant complex. At 6 months of age, G233V mice exhibit a high bone mass phenotype with an approximate doubling of trabecular bone volume in both the tibia and femur. Serum measures of bone resorption were significantly decreased in G233V animals. With decreased bone resorption, cortical thickness was increased, medullary area decreased, and consequently, the mechanical strength of the femur was significantly increased. Using ex vivo bone marrow cultures, osteoclast-specific staining in the G233V mutant marrow was diminished, whereas osteoblastogenesis was unaffected. These studies provide new insights into the relationship between the regulation of megakaryocytopoiesis and bone mass. (Am J

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Transcriptional Program of Mouse Osteoclast Differentiation Governed by the Macrophage Colony-stimulating Factor and the Ligand for the Receptor Activator of NFκB

Abstract: Cytokines macrophage colony stimulating factor (M-CSF

Cited by 172 publications

References 60 publications

Quantitative Proteomics Analysis of the Effects of Ionizing Radiation in Wild Type and p53K317R Knock-in Mouse Thymocytes

Quantitative Proteomics Analysis of the Effects of Ionizing Radiation in Wild Type and p53K317R Knock-in Mouse Thymocytes

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

Platelet Dysfunction and a High Bone Mass Phenotype in a Murine Model of Platelet-Type von Willebrand Disease

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